# NM_021008.4(DEAF1):c.549C>T (p.Pro183=)

https://sugi.bio/variant/deaf1-p-pro183

## Summary

**DEAF1 p.Pro183= (c.549C>T)** is classified **Likely benign** in DEAF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-02). Very rare (popmax 0.00223%, eas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs767648103 · 3 submitters · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the DEAF1 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DEAF1](https://sugi.bio/atlas/gene/DEAF1/) |
| Protein change (HGVS p.) | p.Pro183= |
| Coding change (HGVS c.) | c.549C>T |
| MANE Select transcript | [NM_021008](https://www.ncbi.nlm.nih.gov/nuccore/NM_021008) |
| dbSNP | [rs767648103](https://www.ncbi.nlm.nih.gov/snp/rs767648103/) |
| Variant type | single nucleotide variant |
| Location | chr11:688026-688026 (GRCh38) |
| ClinVar | [VCV585776](https://www.ncbi.nlm.nih.gov/clinvar/variation/585776/) |

**All HGVS expressions:** `NC_000011.10:g.688026G>A`, `NC_000011.9:g.688026G>A`, `NG_034156.2:g.24058C>T`, `NM_001293634.2:c.549C>T`, `NM_001367390.1:c.-178C>T`, `NM_021008.4:c.549C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -7.085, GERP -2.88 — fast-evolving / accelerated position
- CADD: **PHRED 8.078**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.38 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/44,888 in the highest group · 7/1,614,002 alleles overall — very rare (popmax 0.00223%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00223% | 44,888 |
| Admixed American | 0.00167% | 60,002 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,502 |
| South Asian | 0.0011% | 91,068 |
| European (non-Finnish) | 0.000254% | 393,343 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DEAF1** population constraint: LOEUF 1.18, pLI 1.6906e-18, missense-Z 0.83045. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **183** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 61.62, 27% of residues very-high.

**3 experimental structure(s)** (PDB): [2JW6](https://www.rcsb.org/structure/2JW6), [4A24](https://www.rcsb.org/structure/4A24), [5UWW](https://www.rcsb.org/structure/5UWW) — incl. mutant structure 5UWW.

## What this gene does {#gene-function}

*Describes the biological roles of DEAF1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DEAF1's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Pro183= falls in the disordered region.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, DNA-binding transcription repressor activity, RNA polymerase II-specific.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of mammary gland epithelial cell proliferation, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-02.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Likely benign | criteria provided, single submitter | clinical testing | 2018-05-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-02 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-03-12 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related DEAF1 variant pages (same residue, condition, or type): [DEAF1 p.Pro183Leu](/variant/deaf1-p-pro183leu), [DEAF1 c.998-2A>G](/variant/deaf1-c-998-minus-2a-g), [DEAF1 p.Arg224Pro](/variant/deaf1-p-arg224pro), [DEAF1 p.Arg224Trp](/variant/deaf1-p-arg224trp), [DEAF1 p.Arg226Trp](/variant/deaf1-p-arg226trp), [DEAF1 p.Arg246Thr](/variant/deaf1-p-arg246thr), [DEAF1 p.Arg261Ter](/variant/deaf1-p-arg261ter), [DEAF1 p.Arg351Ter](/variant/deaf1-p-arg351ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 585776). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*